AID deficiency greatly improves survival and diminishes renal pathology in the BXSB mouse model of SLE

Abstract

Abstract Eight years have passed since the approval of belimumab, a monoclonal antibody directed against B lymphocyte stimulation and the first targeted therapy approved for systemic lupus. erythematous (SLE). While well tolerated, the efficacy of belimumab remains limited and is not recommended for patients suffering severe nephritis, a life threatening complication of SLE. We sought to explore alternative targets of autoreactive B lymphocytes through manipulation of affinity maturation. The BXSB model is a long established model of human SLE developing elevated antinuclear antibodies and immune complex nephritis along with other manifestations of autoimmune disease. We used CRISPR-Cas9 to inactivate Activation Induced Cytidine Deaminase (Aicda, AID) directly in the BXSB background and found greatly improved survival. While mice continued to develop plasma cells, follicular structure was restored and renal pathology was reduced. While antinuclear antibody concentrations were reduced in knockout mice, renal immune complex deposition was grossly the same as wild type while complement deposition was very limited in the knockout mice. Mice develop expanded germinal center B cell populations as in other models of AID deficiency without concurrent expansion of follicular T cells. The prolonged survival in these mice appears to be attributed to the reduced renal pathology warranting further exploration as current therapeutics targeting lupus nephritis are limited and thus in great demand.